Download HUMAN POPULATION GENETICS population evolution

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HUMAN POPULATION GENETICS
What is population genetics and why is it important?
Theories of Darwin and Mendel & The Modern Synthesis.
population evolution
Population structure and the Hardy-Weinberg theorem.
p2 + 2pq + q2 = 1
Microevolution.
The Neutral Theory of Molecular Evolution.
Dr. A. Ruth Freeman
Department of Genetics
Trinity College Dublin.
Email: [email protected]
www.gen.tcd.ie/molpopgen/ruth
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1) Genetic Drift
Factors that disrupt Hardy-Weinberg
and cause Microevolution
1)
Genetic drift
2)
Gene flow
3)
Mutation
4)
Non-random mating
5)
Natural selection
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• Flip a coin 1000 times Î 700 heads and 300 tails Î very suspicious.
• Flip a coin 10 times Î 7 heads and 3 tails Î well within the bounds of
possibility.
• The smaller the sample, the greater the chance of deviations from the
expected result Î sampling error Îimportant factor in the genetics of
small populations.
• If a new generation draws its alleles at random, then the larger the sample
size, the better it will represent the gene pool of the previous generation.
N.B can act together
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Genetic Drift - population with stable size ~ 10
Generation 1:
p = 0.5
q = 0.5
Genetic Drift - population with stable size ~ 10
Generation 0:
p (frequency of A) = 0.7
q (frequency of a) = 0.3
AA
AA
AA
AA
AA
Aa
Aa
Aa
Aa
aa
AA
aa
AA
Aa
Aa
aa
Aa
Aa
aa
AA
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Genetic Drift
Genetic Drift - population with stable size ~ 10
Generation 2:
p = 1.0
q = 0.0
• In this population of wildflowers, the frequencies of the alleles for
pink and white flowers fluctuate over several generations.
• Only a fraction of the plants manage to leave offspring and over
successive generations, genetic variation Ð (fixed for A allele).
AA
AA
AA
• Microevolution caused by genetic drift, changes in the gene pool of
a small population due to chance.
AA
• Only luck could result in random drift improving the population’s
adaptation to its environment.
AA
AA
AA
• A population must be infinitely large for drift to be ruled out as an
evolutionary process.
AA
• Many populations are so large that drift is negligible.
AA
AA
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Examples of Genetic Drift
The Founder Effect
An extreme form of genetic drift is called the
founder effect.
• Shepard et al. PNAS 2005 102(46):16717-22
Microevolution and mega-icebergs in the Antarctic
Adelie penguins, 6,000 years B.P., 5 loci
It is a particular example of the influence of
random sampling.
• Helgason et al. Ann Hum Genet. 2003 67:281-97
It was defined by Ernst Mayr as:
A reassessment of genetic diversity in Icelanders:
strong evidence from multiple loci for relative
homogeneity caused by genetic drift.
"The establishment of a new population by a
few original founders (in an extreme case,
by a single fertilized female) which carry
only a small fraction of the total genetic
variation of the parental population."
>300,000
Deficit of rare HVS1 sequences – less heterogenous than
other Europeans
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Examples of the founder
effect in humans
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Hum Genet. 1994 94:479-83.
•Fragile X syndrome
in Finland
– single founder
• Amish populations in the USA are
descended from a few dozen
founder individuals and tend to
inter-marry.
•Retinitis pigmentosa on
Tristan da Cunha – 15
British founders
• The result Î they exhibit some
traits at higher frequencies than
the general population, e.g.
polydactyly, microcephaly
•Genghis Khan’s Ychromosome
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The Bottleneck Effect
• Natural calamities can drastically reduce a population - usually unselective.
• The result Î genetic composition of small surviving population Î unlikely
to be representative of the original population.
The Bottleneck Effect I
The
Cheetah
(Acinoyx
jubatus)
originally had a wide range across
Africa and Asia.
Population bottleneck at the end of the
last Ice Age about 10-12000 years ago.
Climate change reduced habitat.
2nd bottleneck during the last 150
years as it was hunted almost to
extinction.
Cheetah are so genetically similar Î
almost like clones.
Alleles in original
population
Bottleneck event
Skin
can
individuals.
Surviving
population
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be
grafted
between
Very susceptible to disease outbreaks.
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The Bottleneck Effect III
The Bottleneck Effect II
The Northern Elephant Seal (Mirounga
angustirostrus) - West coast of
America.
• Modern humans (Homo sapiens sapiens) may also have undergone a
bottleneck ~ 120,000 years ago (very low molecular genetic diversity
compared to chimps, gorillas etc.)
Hunted almost to extinction during the
18th century.
Passed
through
a
population
bottleneck of ~ 20 individuals.
Now population has recovered ~ 30,000
Very low genetic variation. 24 gene loci
examined for polymorphism Î no
variation, fixed for 1 allele at each
gene.
Southern Elephant Seal Î plenty of
variation, was never bottlenecked.
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Gene flow between populations
2) Gene Flow
Fixed for the pink allele
p = 1.0
q = 0.0
• HWE requires the gene pool to be a closed system - most
populations are not completely isolated.
AA
a
• Population can gain or lose alleles by gene flow —genetic
exchange due to migration of fertile individuals or gametes
between populations.
a
a
AA
• Gene flow tends to reduce differences between populations
that have accumulated because of natural selection or genetic
drift.
• If gene flow is extensive enough Î amalgamate neighbouring
populations.
a
AA
AA
a
a
AA
AA
AA
AA
Pollen blown in during a storm
AA
AA
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Gene Flow in Humans
Next generation after gene flow
p = 0.7
q = 0.3
• Many examples.
- African Americans
AA
Aa
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Aa
Aa
- Indian caste system (Lynn Jorde)
AA
Aa
AA
Aa
Aa
AA
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3) Mutation
Mutation in a small wildflower population
• A mutation is a change in an organism’s DNA.
Fixed for the white allele
• New mutation Î transmitted in gametes will immediately change the gene
pool Î either completely new allele or converted to the other allele.
• A mutation that causes the white-flowered plant (aa) to produce gametes
bearing dominant pink allele (A) would decrease freq. of a allele and
increase freq. of A allele.
p = 0.0
q = 1.0
aa
aa
aa
aa
• For any one gene Î mutation does not have much of an effect on a large
population in a single generation.
aa
aa
• Mutation at any given genetic locus is usually very rare.
aa
• Rate of one mutation per 105 - 106 gametes is typical.
aa
• Example: an allele has frequency of 0.5 in the gene pool. Mutates to
another allele at a rate of 0.00001 mutations per generation Î 2000
generations to reduce the frequency of the original allele from 0.50 to 0.49.
aa
aa
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Mutation in a small wildflower population
Next generation:
Mutation
p = 0.05
q = 0.95
aa
aa
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• If a new allele increases its frequency significantly in a
population Î usually because it confers a selective
advantage not because mutation is continually
generating it.
aa
aa
• Mutations at a particular locus Î rare. However,
impact of mutation at all genes is significant - Each
individual: 1000’s of genes.
aa
aa
aa
aa
Aa
• Mutation is the original source of genetic variation Î
raw material for natural selection.
aa
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Examples of Mutations
in Humans
4) Non-random mating.
• For HWE to hold Î individual of any genotype must choose its
mates at random from the population.
Huntington’s chorea –
Lake Maracaibo
• In reality Î individuals usually mate with close neighbours Î
promotes inbreeding.
• Most extreme example of inbreeding Î self-fertilisation (selfing).
Lactose tolerance –
Hollox et al
Am J Hum Genet
2001 68:160-172
• Inbreeding causes relative genotype frequencies to deviate from
HWE.
• Heterozygotes will only produce 50% heterozygotes in the next
generation.
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Complete selfing
Non-random mating - selfing in 24 plants
Generation 0:
Aa
Aa
AA
Aa
p (frequency of A) = 0.5
q (frequency of a) = 0.5
Aa
aa
Aa
aa
AA
AA
AA
aa
aa
AA
Aa
AA
AA
aa
p2 = 0.502 = 0.25 = 6
p2 = 0.502 = 0.25 = 6 (expected)
q2 = 0.502 = 0.25 = 6
q2 = 0.502 = 0.25 = 6 (expected)
AA
aa
aa
AA
Aa
AA
Aa
Aa
AA
aa
Aa
AA
Aa
AA
Aa
aa
AA
Aa
Aa
aa
Aa
Aa
aa
aa
aa
Aa
Aa
AA
Generation 1: p (frequency of A) = 0.5
q (frequency of a) = 0.5
aa
aa
9 observed
9 observed
Not in HWE
2pq = 2 x 0.50 x 0.50 = 0.50 = 12 (expected) 6 observed
2pq = 2 x 0.50 x 0.50 = 0.50 = 12
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Non-random mating in humans
Non-random mating
Inbreeding
• Even in less extreme cases of inbreeding Î proportion of
heterozygotes will decrease (more slowly).
• From a purely phenotypic perspective Î proportion of recessive
phenotypes will increase (white flowered plants).
• This is essentially why inbreeding is not a good idea Î recessive
disorders become more frequent.
• Isolated populations - Amish
• Family systems – European Royals
Assortative mating
• Geography
e.g.
• Another type of nonrandom mating Î assortative mating.
patients with schizophrenia – spouse risk
• Sexual selection
• Assortative mating Î individuals select partners with phenotypic
characters similar to themselves (e.g. height in humans).
e.g.
• Assortative mating Î tend to increase homozygosity at certain
genes.
HLA alleles and olfactory molecules
(Nat Genet 2002 30:175, PNAS 1995 260:245)
Similarity of features (Alvarez & Jaffe 2004 Evol Psych)
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Natural selection in wildflower population with pink mutant
5) Natural selection
G0 allele frequencies
• HWE requires that all individuals in a population be equal in their
ability to survive and produce viable offspring (very unusual in
reality).
aa
aa
• Imagine pink flowers are more visible to pollen-collecting bees.
p = 0.05
q = 0.95
aa
aa
• Over time, the frequency of the A allele will increase and the a allele
will decrease because pink flowers more likely to be visited by bees.
aa
aa
• HWE is disturbed - population is evolving.
• Microevolution
environment.
through
natural
selection
Î
adaptation
aa
to
aa
Aa
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aa
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Natural selection in wildflower population with pink mutant
Natural selection in wildflower population with pink mutant
G1 allele frequencies p = 0.15
q = 0.85
G2 allele frequencies p = 0.30
q = 0.70
Aa
aa
Aa
Aa
aa
aa
aa
Aa
aa
aa
aa
aa
aa
aa
Aa
Aa
AA
aa
Aa
aa
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This kind of selection is also referred to as directional selection
It favours a single allele and may drive it to fixation
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Alternatively balancing selection acts to maintain
genetic polymorphism/multiple alleles in the
population
Most famous classical example is the peppered moth.
Multiple alleles are maintained by:
Common type of peppered moth found
around Manchester pre 19th century is
referred to as typica.
- heterozygote advantage/overdominance
- selective advantage of certain allele combinations
Carbonaria form appeared in 1848, and
reached a frequency of 98% by 1895
- frequency dependent selection – sex ratios
- environmental heterogeneity
New “clean air” laws introduced –
frequency of carbonaria reduced
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Genetic selection in humans I: heterozygote advantage
• Relatively high frequencies of certain alleles that confer reduced
fitness on homozygotes (e.g. cystic fibrosis in Caucasians and
sickle-cell anaemia in Africans) have arisen because the
heterozygotes (Aa) have greater evolutionary fitness than either of
the homozygotes (AA or aa).
• For cystic fibrosis, it seems that heterozygotes are more resistant
to the dehydrating effects of diseases associated with severe
diarrhoea (e.g. cholera).
• For sickle-cell anaemia there is good evidence that heterozygotes
for HbS have increased resistance to death from malarial infection
than the normal HbAHbA homozygotes.
Wild type
Sickle-cell
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Positive selection in humans
• Genes for language – FOXP2
• Genes for brain size - Microcephalin, ASPM Science 2005
(vol 309, p 1717 and p 1720)
Positive selection in some
human populations
• Immunity – esp. malaria
(1920’s - before extensive malaria-control programmes)
• AIM1 in Europeans (Soejima et al 2005 MBE)
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Question
•
In a population that is in HWE, 16% of the individuals show
the recessive trait. What is the frequency of the dominant
allele in the population?
a)
0.84
b)
0.36
c)
0.6
d)
0.4
e)
0.48
REVIEW
Genetic Drift – the founder effect, bottlenecks
Gene Flow
Mutation
Non-random mating
Selection
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Useful Reading
The Essentials of Genetics
by John Murray – Jones Karp Giddings
Biology
by Campbell and Reece – Pearson Education
Principles of Population Genetics
by Daniel L Clark and Andrew G Clark - Sinauer
Genetics of Populations
by Philip W. Hedrick
“Genetics and the origin of species: An introducion”
Ayala and Fitch
PNAS, Vol. 94, p 7691-7697
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